Virtual Substitution Scan Via Single-Step Free Energy Perturbation
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AbstractWith the rapid expansion of our computing power, molecular dynamics (MD) simulations ranging from hundreds of nanoseconds to microseconds or even milliseconds have become increasingly common. The majority of these long trajectories are obtained from plain (vanilla) MD simulations, where no enhanced sampling or free energy calculation method is employed. To promote the "recycling" of these trajectories, we developed the Virtual Substitution Scan (VSS) toolkit as a plugin of the open-source visualization and analysis software VMD. Based on the single-step free energy perturbation (sFEP) method, VSS enables the user to post-process a vanilla MD trajectory for a fast free energy scan of substituting aryl hydrogens by small functional groups. Dihedrals of the functional groups are sampled explicitly in VSS, which improves the performance of the calculation and is found particularly important for certain groups. As a proof-of-concept demonstration, we employ VSS to compute the solvation free energy change upon substituting the hydrogen of a benzene molecule by 12 small functional groups frequently considered in lead optimization. Additionally, VSS is used to compute the relative binding free energy of four selected ligands of the T4 lysozyme. Overall, the computational cost of VSS is only a fraction of the corresponding multi-step FEP (mFEP) calculation, while its results agree reasonably well with those of mFEP, indicating that VSS offers a promising tool for rapid free energy scan of small functional group substitutions. (C) 2016 Wiley Periodicals, Inc.
All Author(s) ListChiang YC, Wang Y
Journal nameBiopolymers
Year2016
Month6
Day1
Volume Number105
Issue Number6
PublisherWILEY-BLACKWELL
Pages324 - 336
ISSN0006-3525
eISSN1097-0282
LanguagesEnglish-United Kingdom
Keywordsfree energy calculation; lead optimization; molecular dynamics; single step FEP
Web of Science Subject CategoriesBiochemistry & Molecular Biology; Biophysics

Last updated on 2020-25-11 at 03:03